Nature Materials ( IF 37.2 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41563-020-0615-x Tito Panciera 1 , Anna Citron 1 , Daniele Di Biagio 1 , Giusy Battilana 1 , Alessandro Gandin 2 , Stefano Giulitti 1 , Mattia Forcato 3 , Silvio Bicciato 3 , Valeria Panzetta 4, 5 , Sabato Fusco 4, 5 , Luca Azzolin 1 , Antonio Totaro 1 , Angelo Paolo Dei Tos 6 , Matteo Fassan 6 , Vincenzo Vindigni 7 , Franco Bassetto 7 , Antonio Rosato 8 , Giovanna Brusatin 2 , Michelangelo Cordenonsi 1 , Stefano Piccolo 1, 9
Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)–Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour emergence. However, RTK–Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell’s environment, such that when cells experience even subtle supra-physiological extracellular-matrix rigidity they are converted into tumour-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies.
中文翻译:
将正常细胞重编程为肿瘤前体细胞需要 ECM 硬度和癌基因介导的细胞机械特性变化
定义正常细胞中启动肿瘤发生所需的遗传事件和微环境之间的相互作用是癌症生物学的核心工作。我们发现受体酪氨酸激酶(RTK)-Ras癌基因将正常的、新移植的原代小鼠和人类细胞重新编程为肿瘤前体细胞,这一过程需要增加癌基因表达细胞与其周围细胞外基质之间的力传递。接近健康组织正常柔软度的微环境或减弱细胞机械传导,可防止癌基因介导的细胞重编程和肿瘤出现。然而,RTK-Ras癌基因使细胞对细胞环境的机械特性产生不成比例的反应,因此当细胞经历甚至微妙的超生理细胞外基质刚性时,它们就会转化为肿瘤起始细胞。这些调节依赖于 YAP/TAZ 机械转导,而 YAP/TAZ 靶基因占致癌信号下游转录反应的很大一部分。这项工作为利用致癌机械信号作为肿瘤发生开始时的脆弱性奠定了基础,包括肿瘤预防策略。